Insulator dysfunction and oncogene activation in IDH mutant gliomas
Flavahan, William A.
Gillespie, Shawn M.
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CitationFlavahan, William A., Yotam Drier, Brian B. Liau, Shawn M. Gillespie, Andrew S. Venteicher, Anat O. Stemmer-Rachamimov, Mario L. Suvà, and Bradley E. Bernstein. 2015. “Insulator dysfunction and oncogene activation in IDH mutant gliomas.” Nature 529 (7584): 110-114. doi:10.1038/nature16490. http://dx.doi.org/10.1038/nature16490.
AbstractGain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas1,2. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7. TET enzymes catalyze a key step in the removal of DNA methylation8,9. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)10,11, though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH mutant gliomas exhibit hyper-methylation at CTCF binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wildtype gliomaspheres up-regulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
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